We have perfected a protocol of inert cryo-ultramicrotomy which permits scanning and transmission electron microscopy of minimally denatured and extracted tissue. With regards to photoreceptor outer segment discs, unstained, freeze-dried cryo-sections demonstrate that the discs are traversed by a complex pattern of 68 degrees oblique sections interspersed between freeze-fractures within the membrane plane. When extensively denatured these periodicities are obliterated which indicate that they initially reflect the native packing of rhodopsin in the membrane. Utilizing the above technique in conjunction with classical EM tissue preparation protocols, we have studied the following three ocular phenomena: (1) The eyes of age matched donors with Zellweger and Conradi syndromes respectively have been studied histologically and ultrastructurally. The most striking similarities are the mitochondrial abnormalities in the RPE and corneal endothelium. (2) Twenty times the normal daily dosage of vitamin E appears to be a suppressant to the ravages of retinopathy of prematurity. In the experimental premature infants, there is always a normal population of mesenchymal spindle cells with no proliferation of the vasculature at the demarcation line. This contrasts with the severe retinopathies which develop ONLY in the control age-matched, weight-matched group. (3) In the rat model, adriamycin and cis-platinum induce photoreceptor atrophy within three weeks post systemic injection such that the RPE is adjacent to an intact inner nuclear layer. At the early post-injection time points (3-7 days), there is a 50 percent shortening of the outer segments. The mechanism and sequence of the later time points is currently being studied.